R&D Day July 13, 2016 Ionis: Creating Value Three - PowerPoint PPT Presentation

R&D Day July 13, 2016

Ionis: Creating Value Three groundbreaking Phase 3 drugs Near-term close to commercialization Advanced, diverse pipeline of first-in- Mid-term class medicines of high value for patients with significant unmet medical need Ionis innovations in technology broaden Long-term utility and enhance value of platform 25

Three Groundbreaking Medicines Close to Commercialization Volanesorsen Nusinersen IONIS-TTR Rx 27

Volanesorsen For Familial Chylomicronemia Syndrome (FCS) and Familial Partial Lipodystrophy (FPL)

Volanesorsen: For Severe, Triglyceride-driven Orphan Diseases with No Treatment Today First and only drug to specifically and robustly reduce Apolipoprotein C-III (ApoCIII) to dramatically decrease triglycerides Potential to improve the life-altering, and in many cases life- threatening, manifestations of FCS and FPL Significant near-term commercial opportunity 30

Two Life-threatening, Genetic, Orphan Diseases Marked by Extreme Triglyceride Levels Risk of potentially fatal pancreatitis FCS FPL   ~3-5k patients worldwide ~3-5k patients worldwide   LPL deficiency, resulting in Inability to store fat, resulting in triglycerides in the 1,000s triglycerides in the 1,000s   Inability to metabolize and clear Disturbance of adipose tissue triglyceride packets resulting in storage resulting in physical chronic pancreatitis abnormalities   Metabolic abnormalities, Extreme insulin resistance, T2DM increased risk of diabetes  Premature death from  Severe lipemia in blood pancreatitis, liver cirrhosis and cardiovascular disease No adequate treatments available 32

Volanesorsen: Ideal Profile as a Potential Treatment for Patients with FCS and FPL Mean Changes -71% to -88% ApoCIII  In FCS patients reduced triglyceride levels up to 86% -64% to -71%  Only drug to specifically lower TG ApoCIII  Improved glucose control, insulin sensitivity Non- -11% to -58% HDL-C  Improved lipid profile including increased HDL-cholesterol HDL-C +42% to +78% Good Cholesterol 42

Nusinersen For Patients with Spinal Muscular Atrophy (SMA)

Nusinersen is Positioned to be the First and Best-in-class Therapy for Infants and Children with SMA SMA is a rare, severe genetic neuromuscular disease defined by progressive muscle atrophy and loss of motor function Ongoing Phase 2 studies show improvements in survival and continued achievement of motor milestones compared to natural history Phase 3 studies in infants and children with SMA fully enrolled and data expected by H1:17 Ionis and Biogen are committed to bringing nusinersen to the market as quickly as possible 65

SMA: Progressive Muscle Atrophy Caused by Genetic Defects in the SMN1 Gene No currently approved therapies – Miller, Survived 87 days – Peter Infantile Onset Childhood Onset  Number one genetic cause of  Shortened life expectancy infant death  Difficulty sitting, raising arms,  Absent of supportive care, most lifting, standing and walking infants will never see their 2nd birthday ~30-35k patients worldwide for all forms of SMA 67

Robust Development Plan to Support Commercialization of Nusinersen Pre- symptomatic Biogen Study Newborns Phase 2 Open Label (Infants) Infant Onset Phase 3 Global Biogen Study Commercial Infant and Childhood Opportunity Onset OLE Study for Phase 3 Studies Phase 3 Childhood Onset Phase 2 Open Label (Children) 87

IONIS-TTR Rx Toward a Treatment for Patients with Transthyretin (TTR) Amyloidosis

TTR Amyloidosis One Disease Caused by the Formation of TTR Amyloid Deposits Leading to Organ Failure Severe, Progressive and Fatal Disease – Fabio – Dawn – Eric TTR Cardiomyopathy FAP  ~10k patients worldwide FAC Wild-type  ~40k patients worldwide  ~200k patients worldwide  Age of onset: 30 – 50  Age of onset: 60 – 70 years  Age of onset: >70 years  TTR amyloid primarily infiltrates peripheral nerves  TTR amyloid primarily infiltrates the heart  Loss of nerve function  Congestive heart failure  Multi-organ failure  Fatal in 3 – 5 years  Fatal in 5 – 15 years 103

IONIS-TTR Rx : Potentially First-in-class and Best-in- class Drug to Treat All Forms of TTR Amyloidosis TTR amyloidosis is a progressive, debilitating, fatal disease caused by TTR amyloid deposits leading to multi-organ failure IONIS-TTR Rx is close to potential filing and launch for patients with familial amyloid polyneuropathy (FAP) Evidence of disease stabilization in patients with TTR cardiomyopathy from an investigator-initiated Phase 2 study GSK is the right development and commercial partner for IONIS-TTR Rx 100

NEURO-TTR Study Summary Robust Phase 3 NEURO-TTR study design  Includes stage 1 and 2 FAP patients with a broad range of genotypes  Majority of patients have both polyneuropathy and cardiomyopathy  Cardiomyopathy analyses will provide data on cardiovascular endpoints Robust and sustained TTR knockdown in patients  Maximum TTR reductions of up to 95% Safety and tolerability profile supports continued development  Study on-track to complete in H1:17  Strong patient retention in NEURO-TTR and robust participation in the OLE  Injection site reactions occurring in approximately 1% of all injections, which were predominantly mild  Very low incidence of serious platelet declines observed in NEURO-TTR  Patients treated over 3 years (and continuing) 118

Ionis Pipeline Value Beyond the Phase 3 Programs Richard Geary, Ph.D., Senior Vice President, Development

Phase 2 Pipeline Poised to Deliver a Broad Range of Transformative Medicines Drugs Indication Partner Phase I Phase II Phase III IONIS-DMPK-2.5 Rx Myotonic Dystrophy 1 Biogen Severe and IONIS-HTT Rx Huntington’s Disease Roche Rare IONIS-SOD1 Rx Amyotrophic Lateral Sclerosis Biogen Hypolipoproteinemia(a) with IONIS-APO(a)-L Rx Ionis/Akcea Premature CVD with Recurrent MACE IONIS-ANGPTL3-L Rx Rare Mixed Dyslipidemias Ionis/Akcea IONIS-FXI Rx Clotting Disorders Bayer IONIS-APO(a)-L Rx Hypolipoproteinemia(a) with CAVS Ionis/Akcea CV IONIS-APO(a)-L Rx Hypolipoproteinemia(a) with CV Risk Ionis/Akcea IONIS-ANGPTL3-L Rx Mixed Dyslipidemias Ionis/Akcea Onco IONIS-AR-2.5 Rx Cancer Ionis IONIS-STAT3-2.5 Rx Cancer AstraZeneca Metabolic IONIS-GCGR Rx Diabetes Ionis IONIS-GCCR Rx Diabetes Ionis IONIS-PTP1B Rx Diabetes Ionis IONIS-FGFR4 Rx Obesity Ionis All Programs in Position to Advance to Phase 3 within the Next 1-3 Years 148

IONIS-FXI Rx : Towards a Safer and More Effective Antithrombotic Generation 2+ Antisense Drug First and only antithrombotic to disassociate prevention of thrombotic events and bleeding risk IONIS-FXI Rx demonstrated a 7-fold lower incidence in VTE in patients undergoing total knee replacement* Well tolerated with no flu-like symptoms and infrequent, mild injection site reactions Commercial potential in wide array of therapeutic settings for which other anticoagulants are not currently effective *Incidence of venous thromboemboli compared to patients treated with enoxaparin undergoing total knee replacement 153

IONIS-GCGR Rx : A Promising New Therapeutic Approach for Type 2 Diabetes Generation 2+ Antisense Drug Potential first-in-class and best-in-class glucagon receptor (GCGR) inhibitor for patients with severe diabetes >2% reduction in HbA1c at 75mg dose and >1% at 50mg dose observed in ongoing Phase 2 study Significant glucose control achieved at lower weekly doses with minimal GCGR-related liver enzyme elevations Well tolerated with no flu-like symptoms and infrequent, mild injection site reactions 158

IONIS-APO(a)-L Rx : The Next Frontier in Cardiovascular Disease Management LICA Drug First and only program to selectively and robustly reduce Lp(a), a key driver of cardiovascular disease LICA technology in IONIS-APO(a)-L Rx increases potency and allows for lower doses and flexibility in dosing frequency Well tolerated with no flu-like symptoms and no injection site reactions observed to date Multi-billion dollar commercial potential targeting both rare and broad patient populations 167

Significant Ongoing Progress in Our Oncology Franchise Multiple durable clinical responses in IONIS-STAT3-2.5 Rx heavily pre-treated patients, including 2 complete responses Multiple durable PSA responses with prolonged stable disease in heavily pre- IONIS-AR-2.5 Rx treated patients with metastatic castration resistant prostate cancer (CRPC) Strategic partnership provides access to MD Anderson MDACC’s novel, traditionally Cancer Center undruggable cancer targets 180

Key Clinical Data Planned in 2016 and Early 2017 Q3:16 Q4:16 Ph. 3 Events H1:17  IONIS-TTR Rx : Ph. 3 Data IONIS-FXI Rx : Nusinersen: Ph. 3 Data for Update in FAP OLE Ph. 2 Data CHERISH  IONIS-TTR Rx : Ph. 2 Data in IONIS-DMPK-2.5 Rx : Nusinersen: Ph. 3 Data for ATTR-CM (Benson) Ph. 1/2 (MAD) Data ENDEAR  IONIS-ANGPTL3-L Rx : IONIS-STAT3-2.5 Rx : IONIS-TTR Rx : Ph. 3 Data Ph. 2 Data Ph. 2 Data for NEURO-TTR  IONIS-GSK4-L Rx Volanesorsen: Ph. 3 Data Ph. 1 (SAD) Data for FCS  IONIS-APO(a)-L Rx Ph. 2 Data  IONIS-GCGR Rx Ph. 2 Data (Interim)  IONIS-AR-2.5 Rx Ph. 2 Data IONIS-DGAT2 Rx : Ph. 1 Data IONIS-FGFR4 Rx : Ph. 2 Data 188

Ionis Technology: Creating Better Medicines and Expanding Opportunities Stanley Crooke, M.D., Ph.D., CEO and Chairman